Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the US. The nuclear receptor Rev-erb? is a transcriptional link between the circadian clock and metabolism, and the present proposal combines tissue-specific, genome-wide analyses of cistromes, transcriptomes, and the epigenome of novel mouse genetic models with sophisticated metabolic phenotyping to understand the physiological role of Rev-erb? in the coordination of circadian rhythms and metabolism. Specific Aim 1 focuses on the role of Rev-erb? in the regulation of hepatic circadian rhythms and metabolism. Genome-wide approaches and deep metabolic phenotyping will test the hypothesis that Rev-erb? controls these processes in a cell- autonomous manner. The effects of gain and loss of function will be compared with loss of DNA binding to understand the spectrum of Rev-erb? action in liver. Specific Aim 2 is to determine the role of brown adipose tissue Rev-erb? in the regulation of circadian rhythms and metabolism. The effects of loss of Rev-erb? in brown adipose tissue (BAT) on energy metabolism will be assessed, and compared with BAT deletion of the epigenomic modulator HDAC3, a component of the nuclear receptor corepressor complex whose effects on BAT function are paradoxically opposite to those of Rev-erb?. Genomic discovery methods will be used to understand the mechanisms by which Rev- erb? and HDAC3 work in opposition to regulate BAT metabolism, while working together to regulate the BAT molecular clock. In Aim 3, we will determine the epigenomic functions of Rev-erb? in the architecture of chromatin, studying the mouse liver to test the hypothesis that Rev-erb? exerts its control over rhythmic gene expression and metabolic physiology in vivo by governing the promoter looping of the circadian enhancers that it controls. These studies will provide a deep understanding of how Rev-erb? acts in the genome to modulate chromatin structure and how that impacts circadian rhythmicity of gene regulation. Together, the integrative studies proposed here will lead to a more fundamental understanding of the links between circadian rhythm and metabolism that underly the mechanisms by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.